Posterior wall isolation in persistent atrial fibrillation feasibility, safety, durability, and efficacy

Abstract Introduction Posterior wall isolation (PWI) added to pulmonary vein isolation (PVI) is increasingly used despite limited evidence of clinical benefit. We investigated the feasibility, durability, and efficacy of index‐procedure PVI + PWI radio frequency ablation (RFA) in patients with persistent atrial fibrillation (PeAF). Methods and Results Twenty‐four patients with PeAF participated in the prospective PeAF‐Box study and underwent RFA with wide area circumferential ablation, roof‐ and inferior lines to achieve PVI + PWI at index procedure. Follow‐up included monitoring by an implantable cardiac monitor, esophagoscopy and mandated invasive lesion‐reassessment at 6 months. PWI was achieved at minor procedural cost in all patients following PVI. In 33% of patients a median of three ablations in the narrow zone between the center of the posterior wall (PW) and the posterior right carina was pivotal for swift achievement of PWI. At the 6‐month reassessment procedure 85% (95% confidence interval [CI]: 77%–92%) of pulmonary veins (PVs) and 46% (95% CI: 26%–67%) of PWs remained durably isolated. AF recurred in 25% and was associated with PV‐reconnection (p = .02) but not PW‐reconnection (p = .27). AF‐burden was 0% (interquartile range [IQR]: 0%–0%) overall and after recurrence 1% (IQR: 0%–7%). Conclusion Index procedure PVI + PWI for PeAF was feasible when recognizing that limited ablation in a PW center‐to‐right‐carina zone was required in a subset of patients. Despite limited chronic PWI durability this strategy was followed by low AF‐burden. A PVI + PWI strategy appears promising in ablation for PeAF.


| INTRODUCTION
Since pulmonary vein isolation (PVI) alone is often inadequate for ablation for persistent atrial fibrillation (PeAF), electrical isolation of the posterior wall (PW) may be rational due to its triggering activity and contribution to the fibrillatory atrial substrate. 1 Earlier, achievement of posterior wall isolation (PWI) by endocardial ablation-despite irrigated tip ablation-was considered challenging, ineffective, and costly in terms of procedure-and fluoroscopy time. 2 Furthermore, the proximity of the esophagus to the PW raised concerns that this strategy may cause esophageal thermal injury (ETI) and atrio-esophageal fistulas to a degree that the PWI strategy was discouraged. 3 A recent meta-analysis on studies spanning a dozen years addressed the feasibility, safety and efficacy of PWI using different ablation techniques. 4 However, little is known about the feasibility of acute PVI + PWI with linear RF ablation using current catheter technology and nothing has been published on PWI durability assessed by prospectively planned invasive reassessment unbiased by clinical status. Furthermore, the impact of PWI on the burden of AF has not been reported. Accordingly, we investigated the acute feasibility and safety of index procedure PVI + PWI and then focused on the efficacy of this strategy determined as the ensuing AF-burden and durability of the lesion set by mandated invasive reassessment after 6 months.

| METHODS
Twenty-four patients with PeAF participated in this prospective study. All had PVI + PWI performed by contact-force sensing guided RFA, implantable cardiac monitor (ICM) implantation day 0, ETI assessed by esophagoscopy day 1, continuous rhythm monitoring with ICM and a protocol-mandated reassessment at 6 months for PV-and PW reconduction. Heart rhythm monitoring continued for 36 months. The study was approved by the Danish National Science Ethics Committee (H15015153) and posted in a national clinical trial database (NCT05045131). All participants provided written informed consent.

| Participants
Participants were recruited between March 2016 and September 2017. Inclusion required highly symptomatic PeAF according to the "atrial fibrillation effect on quality-of-life score" (AFEQT). 5 A list of inclusion-, exclusion criteria and definition of PeAF are given in Table S1. Procedures were performed at a high-volume single center by experienced operators. To suppress procedure-related arrhythmia of unknown clinical relevance, the patients received amiodarone from 3 weeks before to 3 weeks after the procedure. No other antiarrhythmic drugs (AAD) were allowed.

| Ablation procedure
Procedures were preceded by a transesophageal echocardiography and a computed tomography scan of the left atrium (LA) and performed under general anesthesia, continued oral anticoagulation and heparin administered to keep 300 < ACT < 350 s. Esophageal temperatures were monitored with a multiple thermocouple probe (CIRCA S-Cath ® , CIRCA Scientific) and ablation was paused if temperature exceeded 39.5°C. Electroanatomic mapping was performed using CARTO ver. 3 (Biosense Webster ® ).
The LA was accessed via two transseptal sheaths-one of them steerable (Agilis ® , Abbot Laboratories). An anatomical map of the LA was created using the Lasso NAV multielectrode catheters (Biosense ® ) for mapping. Since the focus was PVI + PWI and 46% of patients were in PeAF, voltage maps were not consistently done.
Ablation was performed with a Thermocool Smarttouch catheter (Biosense Webster ® ), with isotonic saline irrigation, guided by catheter contact force and ablation time-the force-time integral (FTI).
PVs were isolated using point-by-point wide antral circumferential ablation (WACA) applying 20-25 W on the PW and 30-35 W elsewhere. An FTI of 400 gram-seconds but no specific impedance drop was targeted. After bidirectional isolation of all PVs, roof and inferior lines connecting the superior and inferior aspects of the WACAs were created using 30 W for the roof line and 20-25 W for the inferior line ( Figure 1). Bidirectional electrical isolation of the PW was ensured by pacing maneuvers confirming lack of signals in the isolated PW measured by multielectrode catheter on the PW during LA pacing and local capture by the multielectrode catheter on the PW without capture of the atria. Ablation of the PW was allowed. Ablation parameters and corresponding maximum esophageal temperatures were collected for each ablation point and assigned to the segments in the model. Dormant conduction to the PVs and PW was tested with repeat adenosine boluses and reconduction was ablated until eradicated. 6 The ICM (Reveal LINQ ® , Medtronic) was inserted subcutaneously and continuous heart rhythm was acquired by the device optimized for AF monitoring as described previously (Table S2). 7

| Follow-up
Esophagoscopy on day 1 was reviewed by a gastroenterologist and lesions were rated according to the Kansas City Classification of esophageal injury post-AF ablation (KCC) where classes 1 (erythema) and 2a (superficial ulceration, fibrin) represent "benign" injury whereas class 2b, 3a, and 3b-with 3b being overt atrioesofageal fistula-are increasingly pernicious. 8 Amiodarone was stopped on day 21 per protocol regardless of rhythm status. Heart rhythm was followed continuously (CareLink ® , Medtronic) and all atrial tachycardia episodes were manually adjudicated and daily AF burden (% of time in AF) was acquired throughout the monitoring period.

| Reassessment procedures
Reassessment procedures were carried out like index procedures. To assess for PV-and PW-reconnection and location of gaps, we created a high-density voltage map with the color display range between 0.20 and 0.50 mV to accentuate border zones and visual identification of gaps between conductive and nonconductive (isolated or scar) myocardium. Bidirectional block of PVs was assessed with reference to both the PW and the remaining LA and bidirectional isolation of the PW was determined. If PVs-or PW were reconnected, the location of gaps was defined by reisolation during ablation or-in case of multiple gaps-a change in activation sequence on the circular catheter deployed in a PV or at the PW endocardium. After reestablishment of PVI + PWI, dormant conduction was assessed as described and counted as regular gaps. Finally, induction of extra-PV/PW trigger activity was attempted by isoprenaline infusion rates 2-10 μg/min for 10 min to achieve heart rates above 100 bpm.

| Study outcomes
The primary outcomes of this exploratory study were (1) The feasibility of the PVI + PWI strategy defined as the ability to achieve bidirectional isolation of the PW within acceptable costs in terms of procedure-, ablation-, and fluoroscopy times and patient radiation exposure. (2) The durability of PVI + PWI defined as the proportion of PVs and PWs remaining durably isolated at invasive reassessment. The AI ® algorithm (ablation index [AI]) became available after study initiation and did not contribute to the ablation strategy.
However, the algorithm was applied post hoc to the original ablation data and AI values adjudicated to each individual ablation point to assess associations between AI and lesion durability.

| Statistics
Though not a primary end point the sample size was chosen to elucidate if ablation at or near the PW to obtain PVI + PWI in a single procedure is safe in terms of the risk of ETI compared to previous findings. With ETI binomially distributed and expectedly less than 10% in our workflow, recruitment of 23 patients would yield 80% power to make probable that single-procedure PVI + PWI is at least as safe with regard to ETI than previously reported. 9 Accordingly we chose to recruit 24 participants. Values are presented according to distribution as mean ± standard deviation or median and interquartile range (Q1-Q3) for continuous data and count and percentage for categorical data unless otherwise stated.
Normally distributed data were compared using Students t tests for unpaired distributions. Non-normally distributed data were compared using the Mann-Whitney test. Statistics were calculated using IBM/SPSS ® ver. 27 software.

| RESULTS
Baseline data are shown in Table 1 Tables 2 and 3. Index procedure PVI + PWI induced low grade asymptomatic ETI in two patients ( Figure S1).  Table S3.

| AF recurrence, AF burden, and conduction gaps
One patient developed atrial tachycardia 87 days after the index procedure, was cardioverted on day 88 and treated with amiodarone between days 109 and 159 (50 days). Otherwise, no patients required cardioversion, AADs or ablation during the 6 months observation period.
ICM-detected recurrence of AF from index procedure +90 days to reassessment was 25% (Figure 3). No patients with completely intact lesion sets (durable PVI + PWI) experienced AF recurrence. Compared to patients with durable PVI + PWI, patients with PV-or combined PV + PW reconduction had significantly higher incidence of AF recurrence (p = .02 for both comparisons) whereas PW reconduction alone was not statistically associated with AF-recurrence (p = .27).
Overall, the AF burden during the 90-day blanking period was median 0.0% (IQR: 0.0%-0.25%) and between end blanking and the reassessment procedure the median AF burden was 0.0%

| DISCUSSION
This is the first prospective study of PVI + PWI using continuous rhythm monitoring by ICM followed by mandated invasive reassessment procedures for lesion durability. Key findings are that single-procedure PVI + PWI was achievable in all patients at minor cost to procedure parameters, when recognizing that limited ablation in a narrow "Center-Right Zone" of the PW was pivotal in a third of the patients. Chronic PWI was, however, limited to approximately 50% and AF recurrence was correlated to PV-and PV + PW reconduction after 6 months. PVI + PWI was associated with a median AF-burden of 0.0% independent of PV-or PW reconduction.

| Feasibility
Acute PWI after PVI was achievable in all patients at minor cost to procedure parameters, which contrasts with earlier attempts to isolate the PW by endocardial ablation lines. Sanders et al. 10 achieved acute PVI + PWI in a "box" fashion by endocardial ablation using 70 min of ablation and 64 min of fluoroscopy. Chen et al. achieved "electrical silence" of the PW using a superior + inferior line approach at the expense of 261 min skin-to-skin time and 46 min fluoroscopy. 11 Importantly they discovered that ablation in the PW was necessary to achieve PWI in 13/42 (31%) of the patients, in line with McLellan et al. 12 where ablation within the boundaries of the "box" was required in 41%. This is consistent with our findings where 33% had residual PW conduction despite the absence of gaps in the roofand inferior lines and required limited PW ablation.
We identified a relatively narrow region between the center of the PW and the posterior right carina-the CRZ (Figures 1 and 2), where a few ablations consistently isolated the entire PW. To our knowledge this has not been reported previously. These CRZablations were pivotal for acute isolation in a third of patients and concomitantly served to avoid widespread PW ablation. This finding is consistent with conductive tissue bypassing the ablation lines inserting directly into the CRZ. It further aligns with anatomical studies emphasizing the importance of muscular sleeves connecting the LA with the PW over the "dome" or roof, where the right limb of the septopulmonary bundle connects to the center-right of the PW. 13 A CRZ-dependent "by-passing" conduction mechanism to the PW is

| Safety
PVI + PWI induced low grade ETI in two patients and accordingly it may be reasonable to expect a low risk of serious esophageal complications by adding PWI in daily practice-even though Thiyagarajah and coworkers found basis for concern in their meta-analysis. 4 Presently roof line ablation appeared safe with respect to esophageal temperatures ( Figure S2), whereas the inferior ablation line might carry a higher risk of jeopardizing the esophagus since maximum temperatures exceeded 40°C in all patterns of esophagus/ LA proximity. This may indicate that future safety-efforts should focus on esophageal protection during inferior line ablation.

| Durability
To date, previous findings on PWI durability during follow-up after an index-procedure "box" isolation approach were biased because reassessments were carried out on clinical indication in a fraction of the ablated patients. 10,12,16 Here, we show that-despite rigorously confirmed acute bidirectional PW isolation-only 46% were durably isolated at mandated invasive reassessment after 6 months.

| Study limitations
The major limitation is the small sample size which hampers generalizability of our findings to all PeAF patients. The sample size was calculated to obtain power for meaningful discussion of risk of ETI-a considerable concern in same-procedure PVI + PWI.